The long range objective of this research is to develop new classes of biologically active compounds based on non-hydrolyzable analogues of sulfate esters that may be used as steroid sulfatase inhibitors, carbo- hydrate sulfatase inhibitors, antisense oligonucleotides, inhibitors of kinases, or structural analogues of important metabolites and cell surface molecules. Specific aims for the next grant period are: (1) Synthesis and Determination of the Biological Activity of Sulfonate Analogues of Sulfate Esters. Sulfated steroids play crucial roles in a variety of cellular processes, most especially the stimulation of breast tumor growth. Our goal is the synthesis and biological testing of sulfonate analogues of steroid sulfates to be used as antitumor agents. Sulfated carbohydrates are also play very important biological roles. We plan to synthesize non-hydrolyzable carbohydrate sulfate analogues as mimics of cell surface carbohydrates. Their ability to inhibit sulfatases and processes dependant on sulfatases, such as fertilization will be tested. (2) Synthesis of Sulfonyl Oligonucleotides as Antisense Inhibitors of Gene Expression. Oligonucleotide analogues have shown great promise as agents for inhibiting the expression of harmful genetic information (i.e. viruses). This proposal details the synthesis of stable non-ionic oligonucleotides using sulfonates, sulfones and sulfonamides in the place of phosphate diesters. (3) Determination of the Biological Activity of Sulfonate Analogues of Phosphate Monoesters. The recognition of sulfonate analogues of glucose 6phosphate, ribose 5-phosphate and the four nucleoside monophosphates by enzymes that use the phosphates as substrates will be tested. Sulfonate analogues of monophosphates are potential mechanism based inactivators of monophosphate kinases.